https://phaidra.vetmeduni.ac.at/o:4293 Hyperactive STAT5 hijacks T cell receptor signaling and drives immature T cell acute lymphoblastic leukemia Suske, Tobias Tobias Suske University of Veterinary Medicine Vienna Sorger, Helena Helena Sorger 0000-0002-3380-7770 University of Veterinary Medicine Vienna Manhart, Gabriele Gabriele Manhart 0000-0001-8714-9550 University of Veterinary Medicine Vienna Ruge, Frank Frank Ruge 0000-0002-4453-8270 University of Veterinary Medicine Vienna Prutsch, Nicole Nicole Prutsch Zimmerman, Mark W. Mark W. Zimmerman Eder, Thomas Thomas Eder 0000-0002-0932-2052 University of Veterinary Medicine Vienna Abdallah, Diaaeldin I Diaaeldin I Abdallah Maurer, Barbara Barbara Maurer University of Veterinary Medicine Vienna Wagner, Christina Christina Wagner 0000-0003-4199-1616 University of Veterinary Medicine Vienna Schönefeldt, Susann Susann Schönefeldt University of Veterinary Medicine Vienna Spirk, Katrin Katrin Spirk University of Veterinary Medicine Vienna Pichler, Alexander Alexander Pichler Pemovska, Tea Tea Pemovska Schweicker, Carmen Carmen Schweicker Pölöske, Daniel Daniel Pölöske 0009-0008-0515-1728 University of Veterinary Medicine Vienna Hubanic, Emina Emina Hubanic Jungherz, Dennis Dennis Jungherz Müller, Tony Andreas Tony Andreas Müller Aung, Myint Myat Khine Myint Myat Khine Aung 0000-0002-3657-9427 University of Veterinary Medicine Vienna Orlova, Anna Anna Orlova 0000-0001-9262-7529 University of Veterinary Medicine Vienna Pham, Ha Thi Thanh Ha Thi Thanh Pham University of Veterinary Medicine Vienna Zimmel, Kerstin Kerstin Zimmel Krausgruber, Thomas Thomas Krausgruber Bock, Christoph Christoph Bock Müller, Mathias Mathias Müller 0000-0002-7879-3552 University of Veterinary Medicine Vienna Dahlhoff, Maik Maik Dahlhoff 0000-0001-9189-7631 University of Veterinary Medicine Vienna Boersma, Auke Auke Boersma 0000-0002-3066-2836 University of Veterinary Medicine Vienna Rülicke, Thomas Thomas Rülicke University of Veterinary Medicine Vienna Fleck, Roman Roman Fleck de Araujo, Elvin Dominic Elvin Dominic de Araujo Gunning, Patrick Thomas Patrick Thomas Gunning Aittokallio, Tero Tero Aittokallio Mustjoki, Satu Satu Mustjoki Sanda, Takaomi Takaomi Sanda Hartmann, Sylvia Sylvia Hartmann Grebien, Florian Florian Grebien 0000-0003-4289-2281 University of Veterinary Medicine Vienna Hoermann, Gregor Gregor Hoermann Haferlach, Torsten Torsten Haferlach Staber, Philipp Bernhard Philipp Bernhard Staber Neubauer-Sedy, Heidi Anne Heidi Anne Neubauer-Sedy 0000-0001-7372-7786 University of Veterinary Medicine Vienna Look, Alfred Thomas Alfred Thomas Look Herling, Marco Marco Herling Moriggl, Richard Richard Moriggl 0000-0003-0918-9463 University of Veterinary Medicine Vienna American Society for Clinical Investigation journal article open access eng T cell acute lymphoblastic leukemia (T-ALL) is an aggressive immature T cell cancer. Mutations in IL7R have been analyzed genetically, but downstream effector functions such as STAT5A and STAT5B hyperactivation are poorly understood. Here, we studied the most frequent and clinically challenging STAT5BN642H driver in T cell development and immature T cell cancer onset and compared it with STAT5A hyperactive variants in transgenic mice. Enhanced STAT5 activity caused disrupted T cell development and promoted an early T cell progenitor-ALL phenotype, with upregulation of genes involved in T cell receptor (TCR) signaling, even in absence of surface TCR. Importantly, TCR pathway genes were overexpressed in human T-ALL and mature T cell cancers and activation of TCR pathway kinases was STAT5 dependent. We confirmed STAT5 binding to these genes using ChIP-Seq analysis in human T-ALL cells, which were sensitive to pharmacologic inhibition by dual STAT3/5 degraders or ZAP70 tyrosine kinase blockers in vitro and in vivo. We provide genetic and biochemical proof that STAT5A and STAT5B hyperactivation can initiate T-ALL through TCR pathway hijacking and suggest similar mechanisms for other T cell cancers. Thus, STAT5 or TCR component blockade are targeted therapy options, particularly in patients with chemoresistant clones carrying STAT5BN642H. http://creativecommons.org/licenses/by/4.0/ https://phaidra.vetmeduni.ac.at/api/object/o:4293/download 10.1172/JCI168536 https://phaidra.vetmeduni.ac.at/o:605 application/pdf Journal of Clinical Investigation issn:1558-8238 VoR Journal of Clinical Investigation 134 8 9.65 MB 2024